P1.12 Frequency of genomic deletion mutations in collagen VI myopathies

mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD. In patient 1 SNP based genomic array analysis revealed a 69 kb genomic deletion at 21q22.3 encompassing at least 18 exons of the COL6A2 gene on one allele. Exonic sequencing of the non-deleted allele found an intronic nucleotide change (G > A) at position c.1970-9. cDNA sequencing of COL6A2 revealed a 7 base pair insertion resulting from the use of a novel splice acceptor site in intron 25 created by the mutation, resulting in a frameshift and a premature stop codon (G656AfsX17). Patient 1’s asymptomatic mother is heterozygous for (G > A) at c.1970-9 of COL6A2; his asymptomatic father is heterozygous for the 69 kb deletion. Patient 2 has two genomic deletions at 21q22.3: a deletion of 1.61Mb encompassing the entire COL6A1 and COL6A2 genes plus surrounding genes on one allele and a smaller deletion of 47 kb encompassing the entire COL6A2 gene on the other allele. Patient 2’s asymptomatic mother is heterozygous for the 1.61Mb deletion; his asymptomatic father is heterozygous for the 47 kb deletion. In addition, we incidentally identified an asymptomatic father and his son who are heterozygous for a 1.09Mb deletion of both the COL6A1 and COL6A2 loci but do not carry a mutation on the other allele and, therefore, do not manifest signs of the disease. Large genomic deletions add to the complexity of genetic evaluations in the collagen VI related myopathies. Clinically unaffected parents carrying large genomic deletions of COL6A1 and COL6A2 provide conclusive evidence that haploinsufficiency for COL6A1 and COL6A2 does not result in clinical neuromuscular disease and, in particular, is not a disease mechanism for Bethlem myopathy.